The present invention concerns N-[4-(heteroaryl-methyl)phenyl]-heteroarylamines, their N-oxides and addition salts; it further relates to processes for their preparation, and compositions comprising them. The compounds of the present invention are potent inhibitors of the retinoic acid-metabolism, and hence, their use as a medicine is also described.
EP-A-0,260,744, published on Mar. 23, 1988, discloses (1H-imidazol-1-ylmethyl) substituted benzimidazoles as inhibitors of the androgen formation from C21-steroids, as inhibitors of the biosynthesis of thromboxane A2, and also having the capability to increase the excretion of ureic acid. EP-A-0,371,559, published on Jun. 6, 1990, discloses said benzimidazoles and analogous benzotriazoles as potent suppressers of the plasma elimination of endogenously or exogenously administered retinoic acid.
Retinoic acid (RA) is a key molecule in the regulation of growth and differentiation of epithelial tissues. However, RA is very rapidly metabolized by a series of enzymatic reactions, which results in its deactivation. Inhibition of RA-metabolism leads to enhanced RA levels in plasma and tissue. Therefore, compounds with such an inhibitory action, also called retinoic mimetic activity, have therapeutic and/or preventive potential in the field of dermatology and oncology.
The novel compounds of the present invention have retinoic mimetic activity and, moreover, show little or no endocrinological side-effects.
The present invention is concerned with compounds of formula 
the N-oxides, the pharmaceutically acceptable addition salts and the stereochemically isomeric forms thereof, wherein:
R1 represents hydrogen, hydroxy, C1-6alkyl or aryl;
R2 represents hydrogen; C1-12alkyl; C3-7cycloalkyl; C2-8alkenyl; aryl; pyrrolidinyl optionally substituted with C1-4alkyl or C1-4alkyloxycarbonyl; or C1-12alkyl substituted with one or two substituents selected from C3-7cycloalkyl, hydroxy, C1-4alkyloxy, cyano, amino, mono- and di(C1-4alkyl)amino, mono- and di(aryl)-amino, arylC1-4alkylamino, (C1-4alkyl)(arylC1-4alkyl)amino, pyrrolidinyl, piperidinyl, piperazinyl optionally substituted with C1-4alkyl, morpholinyl, perhydro-azepinyl, carboxyl, C1-4alkyloxycarbonyl, aminocarbonyl, mono- and di(C1-4alkyl)aminocarbonyl, aryl, aryloxy and arylthio;
R3 represents hydrogen, C1-6alkyl, aryl or C1-6alkyl substituted with aryl;
Het represents an unsaturated heterocycle selected from imidazolyl, triazolyl, tetrazolyl and pyridinyl; each of said unsaturated heterocycles may optionally be substituted with amino, mercapto, C1-6alkyl, C1-6-alkylthio or aryl; 
represents an unsaturated mono- or bicyclic heterocycle selected from the group consisting of pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, quinolinyl, isoquinolinyl, purinyl, phtalazinyl, cinnolinyl, quinazolinyl and quinoxalinyl; each of said unsaturated mono- or bicyclic heterocycles may optionally be substituted with one, two or three substituents selected from hydroxy, halo, nitro, amino, C1-6alkyl, hydroxyC1-6alkyl, haloC1-6alkyl, C1-6alkyloxy, C1-6alkylthio, formyl, carboxyl, mono- or di(C1-6alkyl)amino, C1-6alkyloxycarbonyl or aryl; or 
represents a radical of formula 
wherein:
each X independently represents NR8, O, S, S(xe2x95x90O) or S(xe2x95x90O)2; wherein R8 is hydrogen, C1-6alkyl, aryl or arylC1-6alkyl;
R4 and R5 each independently represent hydrogen, hydroxy, halo, cyano, nitro, amino, C1-6alkyl, hydroxyC1-6alkyl, haloC1-6alkyl, C1-6alkyloxy, formyl, carboxyl, mono- or di(C1-6alkyl)amino, C1-6alkyloxycarbonyl or aryl;
xe2x80x94R6xe2x80x94R7xe2x80x94 represents a bivalent radical of formula:
xe2x80x83wherein each R9 independently represents hydrogen, hydroxy, halo, nitro, amino, C1-6alkyl, hydroxyC1-6alkyl, haloC1-6alkyl, C1-6alkyloxy, formyl, carboxyl, mono- or di(C1-6alkyl)amino, C1-6alkyloxycarbonyl or aryl; and
aryl represents phenyl or phenyl substituted with one, two or three substituents selected from hydroxy, halo, cyano, amino, mono- or di(C1-6alkyl)amino, C1-6alkyl, haloC1-6alkyl, hydroxyC1-6alkyl, C1-6alkyloxy, formyl, carboxyl and C1-6alkylcarbonyl; or two adjacent carbon atoms on said phenyl may be substituted by a single bivalent radical having the formula C1-12alkanediyl or haloC1-12alkanediyl.
As used in the foregoing definitions and hereinafter, halo is generic to fluoro, chloro, bromo and iodo; C3-7cycloalkyl is generic to cyclopropyl, cyclobutyl, cyclopentyl cyclohexyl and cycloheptyl; C2-8alkenyl defines straight and branch chained hydrocarbon radicals containing one double bond and having from 2 to 8 carbon atoms such as, for example, ethenyl, 1-propenyl, 2-butenyl, 2-pentenyl, 3-pentenyl, 3-methyl-2-butenyl, 3-hexenyl, 3-heptenyl, 2-octenyl and the like; C1-4alkyl defines straight and branched chain saturated hydrocarbon radicals having from 1 to 4 carbon atoms such as, for example, methyl, ethyl, propyl, butyl, 1-methylethyl, 2-methylpropyl, 2,2-dimethylethyl and the like; C1-6alkyl is meant to include C1-4alkyl and the higher homologues thereof having 5 or 6 carbon atoms such as, for example, pentyl, 2-methylbutyl, hexyl, 2-methylpentyl and the like; C1-12alkyl is meant to include C1-6alkyl and the higher homologues having from 7 to 12 carbon atoms such as, for example, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, 2-methylhexyl, 3-ethyloctyl and the like; C1 12alkanediyl defines bivalent straight and branched chain saturated hydrocarbon radicals having from 1 to 12 carbon atoms such as, for example, 1,1-methanediyl, 1,2-ethanediyl, 1,3-propanediyl, 1,4-butanediyl, 1,5-pentanediyl, 1,6-hexanediyl, 1,2-propanediyl, 2,3-butanediyl, 1,7-heptanediyl, 1,8-octanediyl, 1,9-nonanediyl, 1,10-decanediyl, 1,11-undecanediyl, 1,12-dodecanediyl, 1,1,4,4,-tetra-methylbutane-1,4-diyl and the like; haloC1-6alkyl is defined as polyhalosubstituted C1-6alkyl, in particular C1-6alkyl substituted with 1 to 6 halogen atoms, more in particular difluoro- or trifluoromethyl; haloC1-12alkanediyl is defined as polyhalo-substituted C1-12alkanediyl, in particular C1-12alkanediyl substituted with 1 to 12 halogen atoms; triazolyl is meant to include 1,2,4-triazolyl and 1,3,4-triazolyl; tetrazolyl is meant to include 1H-tetrazolyl and 2H-tetrazolyl.
The unsaturated heteroaryl group represented by Het may be attached to the remainder of the molecule of formula (I) through any ring carbon or heteroatom as appropriate. Thus, for example, when the heteroaryl group is imidazolyl, it may be a 1-imidazolyl, 2-imidazolyl, 4-imidazolyl and 5-imidazolyl; when it is triazolyl, it may be 1,2,4-triazol-1-yl, 1,2,4-triazol-3-yl, 1,2,4-triazol-5-yl, 1,3,4-triazol-1-yl and 1,3,4-triazol-2-yl.
The pharmaceutically acceptable addition salts as mentioned hereinabove are meant to comprise the therapeutically active nontoxic base and acid addition salt forms which the compounds of formula (I) are able to form. The acid addition salt form of a compound of formula (I) that occurs in its free form as a base can be obtained by treating said free base form with an appropriate acid such as an inorganic acid, for example, hydrohalic acid, e.g. hydrochloric or hydrobromic, sulfuric, nitric, phosphoric and the like acids; or an organic acid, such as, for example, acetic, hydroxyacetic, propanoic, lactic, pyruvic, oxalic, malonic, succinic, maleic, fumaric, malic, tartaric, citric, methanesulfonic, ethanesulfonic, benzenesulfonic, p-toluenesulfonic, cyclamic, salicylic, p-aminosalicylic, pamoic and the like acids.
The compounds of formula (I) containing acidic protons may be converted into their therapeutically active non-toxic base, i.e. metal or amine, addition salt forms by treatment with appropriate organic and inorganic bases. Appropriate base salt forms comprise, for example, the ammonium salts, the alkali and earth alkaline metal salts, e.g. the lithium, sodium, potassium, magnesium, calcium salts and the like, salts with organic bases, e.g. the benzathine, N-methyl-D-glucamine, hydrabamine salts, and salts with amino acids such as, for example, arginine, lysine and the like.
Conversely said salt forms can be converted into the free forms by treatment with an appropriate base or acid.
The term addition salt as used hereinabove also comprises the solvates which the compounds of formula (I) as well as the salts thereof, are able to form. Such solvates are for example hydrates, alcoholates and the like.
The N-oxide forms of the compounds of formula (I) are meant to comprise those compounds of formula (I) wherein one or several nitrogen atoms are oxidized to the so-called N-oxide.
The term xe2x80x9cstereochemically isomeric formsxe2x80x9d as used hereinbefore and hereinafter defines all the possible isomeric forms in which the compounds of formula (I) may occur. Unless otherwise mentioned or indicated, the chemical designation of compounds denotes the mixture, and in particular the racemic mixture, of all possible stereochemically isomeric forms, said mixtures containing all diastereomers and enantiomers of the basic molecular structure. Stereochemically isomeric forms of the compounds of formula (I) and mixtures of such forms are obviously intended to be encompassed by formula (I).
In particular, the compounds of formula (I) and some of the intermediates hereinafter have at least one stereogenic center in their structure. This stereogenic center may be present in a R and a S configuration, said R and S notation is used in correspondance with the rules described in Pure Appl. Chem., 1976, 45, 11-30.
Some of the compounds of formula (I) may also exist in their tautomeric forms. Such forms although not explicitly in the above formula are intended to be included within the scope of the present invention. In particular, compounds of formula (I) wherein R3 is hydrogen may exist in their corresponding tautomeric form.
Whenever used hereinafter, the term compounds of formula (I) is meant to include also the N-oxides, the pharmaceutically acceptable addition salts and all stereoisomeric forms.
A particular group of compounds comprises those compounds of formula (I) wherein
R1 represents hydrogen, C1-6alkyl or aryl;
R2 represents hydrogen; C1-12alkyl; C3-7cycloalkyl; C2-8-alkenyl; aryl; or C1-12alkyl substituted with one or two substituents selected from C3-7cyclo-alkyl, hydroxy, C1-4alkyloxy, cyano, amino, mono- and di(C1-4alkyl)amino, mono- and di(aryl)amino, arylC1-4alkylamino, (C1-4alkyl)C1-4alkyl)-amino, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, perhydro-azepinyl, carboxyl, C1-4alkyloxycarbonyl, aminocarbonyl, mono- and di(C1-4alkyl)aminocarbonyl, aryl, aryloxy and arylthio; 
represents an unsaturated mono- or bicyclic heterocycle selected from the group consisting of 2-pyridinyl, 3-pyridazinyl, 2-pyrimidinyl, 4-pyrimidinyl, 2-pyrazinyl, 2-quinolinyl, 1-isoquinolinyl, 3-isoquinolinyl, 1-phtalazinyl, 3-cinnolinyl, 2-quinazolinyl, 4-quinazolinyl and 2-quinoxalinyl; each of said unsaturated mono- or bicyclic heterocycles may optionally be substituted with one, two or three substituents selected from hydroxy, halo, nitro, amino, C1-6alkyl, hydroxyC1-6alkyl, haloC1-6alkyl, C1-6alkyloxy, formyl, carboxyl, mono- or di(C1-6alkyl)amino, C1-6alkyloxycarbonyl or aryl; or 
represents a radical of formula (a) or (b) wherein R4 and R5 each independently represent hydrogen, hydroxy, halo, nitro, amino, C1-6alkyl, hydroxy-C1-6alkyl, haloC1-6alkyl, C1-6alkyloxy, formyl, carboxyl, mono- or di(C1-6alkyl)-amino, C1-6alkyloxycarbonyl or aryl.
A group of interesting compounds comprises those compounds of formula (I) wherein
R1 represents hydrogen, hydroxy, C1-6alkyl;
R2 represents hydrogen; C1-12alkyl; C3-7cycloalkyl; pyrrolidinyl optionally substituted with C1-4alkyl or C1-4alkyloxycarbonyl; aryl or C1-12alkyl substituted with one or two substituents selected from hydroxy, C1-4alkyloxy, mono- and di(C1-4alkyl)amino, (C1-4alkyl)(arylC1-4alkyl)amino, C1-4alkyloxycarbonyl, morpholinyl, piperidinyl, piperazinyl optionally substituted with C1-4alkyl, and aryloxy;
R3 represents hydrogen and C1-6alkyl;
Het represents imidazolyl optionally substituted with C1-6alkyl; pyridinyl or triazolyl; 
represents 2-pyridinyl optionally substituted with hydroxyC1-6alkyl, formyl or C1-6alkyloxycarbonyl; 2quinoxalinyl; 1-isoquinolinyl; 2-quinolinyl; 3-pyridazinyl optionally substituted with C1-6alkyl; purinyl; 2-pyrazinyl; 1-phtalazinyl; 4-quinazolinyl optionally substituted with aryl; 2-pyrimidinyl; 4-pyrimidinyl optionally substituted with C1-6alkylthio; or 
represents a radical of formula (a) or (b), wherein:
X represents NH, O or S;
R4 and R5 each independently represent hydrogen, hydroxy, nitro, cyano, amino, C1-6alkyl or aryl;
xe2x80x94R6xe2x80x94R7xe2x80x94 represents a bivalent radical of formula (b-1), (b-2) or (b-10), wherein each R9 independently represents hydrogen, C1-6alkyl, hydroxy, halo, amino, haloC1-6alkyl or C1-6alkyloxy.
Of special interest are those compounds of formula (I) wherein Het is optionally substituted imidazolyl or triazolyl, in particular, 1-imidazolyl optionally substituted with C1-6alkyl or aryl; 2-imidazolyl optionally substituted with C1-6alkyl; 5-imidazolyl optionally substituted with C1-6alkyl; 1,3,4-triazol-1-yl and 1,2,4-triazol-1-yl.
Also of special interest are those compounds of formula (I) wherein 
represents a radical of formula (b), particularly those wherein
X represents O or S; and
xe2x80x94R6xe2x80x94R7xe2x80x94 represents a bivalent radical of formula (b-1).
Other compounds of special interest are those compounds of formula (I) wherein R2 represents C1-12alkyl; C3-7cycloalkyl; aryl or C1-12alkyl substituted with mono- or di(C1-4alkyl)amino, C1-4alkyloxycarbonyl or aryloxy.
Particular compounds are those compounds of special interest wherein Het is 1-imidazolyl optionally substituted with C1-6alkyl or aryl; 2-imidazolyl optionally substituted with C1-6alkyl; 5imidazolyl optionally substituted with C1-6alkyl; 1,3,4-triazol-1-yl and 1,2,4-triazol-1-yl; R2 represents C1-12alkyl; C3-7cycloalkyl; aryl or C1-12alkyl substituted with mono- or di(C1-4alkyl)amino; and 
represents a radical of formula 
wherein X represents O or S.
Preferred compounds are those compounds of formula (I) wherein R1 is hydrogen and R2 is C3-7cycloalkyl or C1-6alkyl optionally substituted with di(C1-6alkyl)amino.
Most preferred are the compounds
N-[4-[2-ethyl-1-(1H-imidazol-1-yl)butyl]phenyl]-2-benzothiazolamine;
N-[4-[2-ethyl-1-(1H-1,2,4-triazol-1-yl)butyl]phenyl]-2-benzoxazolamine;
N-[4-[2-ethyl-1-(1H-1,2,4-triazol-1-yl)butyl]phenyl]-2-benzothiazolamine;
N-[4-[2-(dimethylamino)-1-(1H-imidazol-1-yl)propyl]phenyl]-2-benzothiazolamine:
N-[4-[2-(dimethylamino)-1-(1H-1,2,4-triazol-1-yl)propyl]phenyl]-2-benzothiazolamine;
N-[4-[2-ethyl-1-(1H-imidazol-1-yl)butyl]phenyl]-2-benzoxazolamine;
N-[4-[2-ethyl-1-(1H-imidazol-1-yl)butyl]phenyl]-6-methoxy-2-benzothiazolamine:
N-[4-[2-(dimethylamino)-1-(1H-imidazol-1-yl)-2-methylpropyl]phenyl]-2-benzothiazolamine;
N-[4-[2-(dimethylamino)-2-methyl-1-(1H-1,2,4-triazol-1-yl)propyl]phenyl]-2-benzothiazolamine;
N-[4-[-cyclohexyl(1H-imidazol-1-yl)methyl]phenyl]-2-benzothiazolamine;
N-[4-[-cyclohexyl(1H-1,2,4-triazol-1-yl)methyl]phenyl]-2-benzothiazolamine; the N-oxides, the stereochemically isomeric forms and the pharmaceutically acceptable addition salts thereof.
Whenever used hereinafter, R1 to R3, Het, aryl and 
are defined as under formula (I) unless otherwise indicated.
In general, the compounds of formula (I) can be prepared by reacting an intermediate of formula (II) wherein W1 is an appropriate leaving group such as, for example, a halogen, hydroxy or an alkylsulfonyloxy group, with an intermediate of formula (III) or a functional derivative thereof. For instance, a functional derivative of imidazole may be 1,1xe2x80x2-carbonyldiimidazole. 
Said reaction may be performed in a reaction-inert solvent such as, for example, acetonitrile or tetrahydrofuran, in the presence of a suitable base such as, for example, potassium carbonate. In case W1 is an hydroxy group, it nay be convenient to perform the above reaction in the presence of triphenylphosphine and diethyl azodicarboxylate or a functional derivative of any of said reagents.
In this and the following preparations, the reaction products may be isolated from the reaction medium and, if necessary, further purified according to methodologies generally known in the art such as, for example, extraction, crystallization, distillation, trituration and chromatography.
Alternatively, compounds of formula (I) may be prepared by N-alkylation of an intermediate of formula (IV) with an intermediate of formula (V) wherein W2 is an appropriate leaving group such as, for example, a phenoxy group, in a reaction-inert solvent such as, for example, N,N-dimethylformamide. 
Compounds of formula (I) wherein 
is a radical of formula (a) wherein X represents S, said compounds being represented by formula (I-a-1), can be prepared by reacting an intermediate of formula (VI) with an intermediate of formula (VII) wherein W3 is an appropriate leaving group and in a reaction-inert solvent such as, for example, tetrahydrofuran. 
Suitably, intermediates of formula (VII) may be replaced by a functional derivative thereof such as, for example, the ketalized derivative thereof. In case the carbonyl group in the intermediates of formula (VII) is ketalized, the reaction is suitably performed in the presence of an acid such as, for example, hydrochloric acid.
The compounds of formula (I) wherein R3 is hydrogen and 
is a radical of formula (b) wherein X represents S, said compounds being represented by formula (I-b-1), can be prepared by reacting an intermediate of formula (VIII) with an intermediate of formula (IX-1) in a reaction-inert solvent such as, for example, tetrahydrofuran or 1-methyl-2-pyrrolidinone. 
In the above reaction, intermediate (IX-1) may be replaced by an intermediate of formula (IX-2) thus forming a compound of formula (I-a-1) wherein R3 is hydrogen and R4 is amino, said compounds being represented by formula (I-a-2). 
As an alternative to intermediate (VIII), the reaction may also be performed using an intermediate of formula (X). Said reaction is then performed in a reaction-inert solvent such as, for example, dimethylsulfoxide, and in the presence of a suitable base such as, for example, sodium hydroxide. 
Compounds of formula (I) wherein R1 is hydroxy may be prepared by reacting an intermediate corresponding to a compound of formula (I) wherein R1 and R2 together with the carbon atom to which they are attached form a carbonyl group, with Het-H (III) or a functional derivative thereof, in the presence of an appropriate reagent such as, for example, n-butyllithium, in a reaction-inert solvent such as tetrahydrofuran, and optionally in the presence of chlorotriethylsilane.
Compounds of formula (I) wherein R2 is C1-6alkyloxyC1-12alkyl can be prepared by reacting an intermediate corresponding to a compound of formula (I) wherein R2 is L-C1-12alkyl wherein L is an appropriate leaving group such as, for example, a alkylsulfonyloxy group, with C1-4alkylOxe2x88x92M+ wherein M+ is a suitable metal ion such as, for example Na+, in a suitable solvent such as methanol.
Compounds of formula (I) wherein R2 is optionally substituted C1-12alkyl can be prepared by reducing an intermediate corresponding to a compound of formula (I) wherein said R2 is connected to the carbon atom bearing the R2 substituent by a double bond using a suitable reducing agent such as, for example, sodiumborohydride, in a suitable solvent such as methanol.
The compounds of formula (I) can also be converted into each other following art-known procedures of functional group transformation.
For example, compounds of formula (I) wherein R3 is hydrogen may be converted to compounds of formula (I) wherein R3 is other than hydrogen.
Also, compounds of formula (I) containing a C1-6alkyloxycarbonyl substituent, may be transformed to compounds of formula (I) wherein said substituent is reduced to hydroxymethyl; and if desired, said hydroxymethyl substituent may be further transformed to a formyl group.
Compounds of formula (I-a-2) wherein R5 is cyano can be further reacted with HNxe2x95x90CHxe2x80x94NH2 or a functional derivative thereof, thus forming the corresponding compound of formula (I-b-1) wherein xe2x80x94R6xe2x80x94R7xe2x80x94 is xe2x80x94Nxe2x95x90CHxe2x80x94Nxe2x95x90C(NH2)xe2x80x94.
Compounds of formula (I) wherein R1 is hydroxy can be converted to compounds of formula (I) wherein R1 is hydrogen using a suitable reagent such as stannous chloride.
The compounds of formula (I) may also be converted to the corresponding N-oxide forms following art-known procedures for converting a trivalent nitrogen into its N-oxide form. Said N-oxidation reaction may generally be carried out by reacting the starting material of formula (I) with 3-phenyl-2-(phenylsulfonyl)oxaziridine or with an appropriate organic or inorganic peroxide. Appropriate inorganic peroxides comprise, for example, hydrogen peroxide, alkali metal or earth alkaline metal peroxides, e.g. sodium peroxide, potassium peroxide; appropriate organic peroxides may comprise peroxy acids such as, for example, benzenecarboperoxoic acid or halo substituted benzenecarboperoxoic acid, e.g. 3-chlorobenzenecarboperoxoic acid, peroxoalkanoic acids, e.g. peroxoacetic acid, alkylhydroperoxides, e.g. t-butyl hydroperoxide. Suitable solvents are, for example, water, lower alkanols, e.g. ethanol and the like, hydrocarbons, e.g. toluene, ketones, e.g. 2-butanone, halogenated hydrocarbons, e.g. dichloromethane, and mixtures of such solvents.
Some of the compounds of formula (I) and some of the intermediates in the present invention may contain an asymmetric carbon atom. Pure stereochemically isomeric forms of said compounds and said intermediates can be obtained by the application of art-known procedures. For example, diastereoisomers can be separated by physical methods such as selective crystallization or chromatographic techniques, e.g. counter current distribution, liquid chromatography and the like methods. Enantiomers can be obtained from racemic mixtures by first converting said racemic mixtures with suitable resolving agents such as, for example, chiral acids, to mixtures of diastereomeric salts or compounds: then physically separating said mixtures of diastereomeric salts or compounds by, for example, selective crystallization or chromatographic techniques, e.g. liquid chromatography and the like methods; and finally converting said separated diastereomeric salts or compounds into the corresponding enantiomers. Pure stereochemically isomeric forms may also be obtained from the pure stereochemically isomeric forms of the appropriate intermediates and starting materials, provided that the intervening reactions occur stereospecifically.
An alternative manner of separating the enantiomeric forms of the compounds of formula (I) and intermediates involves liquid chromatography, in particular liquid chromatography using a chiral stationary phase.
Some of the intermediates and starting materials are known compounds and may be commercially available or may be prepared according to art-known procedures.
In particular, intermediates of formula (II) wherein R1 and R3 are hydrogen, W1 is hydroxy and 
is a radical of formula (b), said intermediates being represented by formula (II-b-1), may be prepared by reacting an intermediate of formula (IX) with an intermediate of formula (XI-1) or (XI-2), and subsequently reducing the thus formed intermediate. 
The first reaction involves the same procedure as the one used hereinabove for the preparation of compounds of formula (I-b-1) starting from an intermediate of formula (IX) and an intermediate of formula (VIII) or (X). The reduction may be performed in the presence of a suitable reducing agent in an appropriate reaction-inert solvent such as, for example, sodiumborohydride in methanol or lithiumaluminiumhydride in tetrahydrofuran and water.
In some instances, it may be convenient to replace the hydroxy group in intermediates of formula (II-b-1) by another leaving group such as, for example, a halogen or a sulfonyl derivative, e.g. a p-toluenesulfonyloxy group or a alkylsulfonyloxy group, thus forming intermediates of formula (II-b-2) or (II-b-3). Said reaction can be performed in a reaction-inert solvent, such as, for example, chloroform, and in the presence of a suitable agent such as, for example, thionylchloride or methylsulfonyl chloride. 
Intermediates of formula (IV) may be prepared by reacting an intermediate of formula (XII), wherein P is a protective group such as, for example, C1-4alkylcarbonyl, benzoyl or C1-4alkyloxycarbonyl, with an intermediate of formula (III), and by subsequently reacting the thus formed amide derivative with an acid such as, for example, hydrochloric acid. The preparation of the intermediate amide derivative may be performed using the same procedure as the one used for the preparation of compounds of formula (I) starting form an intermediate of formula (II) and (III). 
Intermediates of formula (VI) can be prepared by further reacting an intermediate of formula (IV) with a combination of two suitable reagents such as, for example, NH4SCN in combination with benzoylchloride or a functional derivative of any one of said reagents, in a reaction-inert solvent such as, for example, 2-propanone. The thus formed intermediate may be deprotected using a suitable base such as, for example, sodium hydroxide. 
Intermediates of formula (IV) wherein R3 is hydrogen, said intermediates being represented by formula (IV-a), may also be reacted with an appropriate reagent such as CSCl2 or a functional derivative thereof, in a reaction inert solvent and in the presence of a suitable base such as, for example, sodium hydroxide, thus forming intermediates of formula (VIII). 
Also, intermediates of formula (IV-a) may further be used in the preparation of intermediates of formula (X). Said preparation involves the reaction of an intermediate of (IV-a) with CS2 and CH3xe2x80x94I or a functional derivatives of any one of said reagents, in a reaction-inert solvent and in the presence of a base such as, for example, sodium hydroxide. 
The compounds of formula (I) suppress the plasma elimination of retinoids, such as all-trans-retinoic acid, 13-cis retinoic acid and their derivatives, resulting in more sustained plasma and tissue concentrations of retinoic acid and improved control of the differentiation and growth of various cell types. This action of the present compounds is also called retinoic mimetic activity because administering a compound of formula (I) causes the same effect as if retinoids were administered. As such, the present compounds can be used to control the rate of growth and differentiation of normal, preneoplastic and neoplastic cells, whether they are epithelial or mesenchymal; whether they are of ectodermal, endodermal or mesodermal origin.
The property to delay the metabolism of retinoic acid can be evidenced in various in vitro and in vivo experiments. A polar in vitro procedure is described in example C.1 and tests the inhibitory activity of the compounds of formula (I) on the metabolism of retinoic acid human breast cancer cells. The compounds of the present invention were also effective in suppressing induced vaginal keratinization effects in ovariectomized rats as is described in example C.2.
In addition, the compounds of formula (I) show little or no endocrinological side-effects and they have good oral availability.
In view of the above described pharmacological properties, in particular their retinoic mimetic activity, the present compounds are useful in the treatment and/or the prevention of disorders characterized by abnormal proliferation and/or abnormal differentiation of cells, in particular of cells of which the growth and differentiation is sensitive to the actions of retinoids. Such disorders are situated in the field of oncology, for example, head- and neck cancer, lung cancer, breast cancer, uterine cervix cancer, gastrointestinal tract cancer, skin cancer, bladder cancer and prostate cancer and similar disorders; and in the field of dermatology, for example, keratinization disorders such as rosacea, acne, psoriasis, severe psoriasis, lamellar ichthyosis, plantar warts, callosities, acanthosis nigricans, lichen planus, molluscum, melasma, corneal epithelial abrasion, geographic tongue, Fox-Fordyce disease, cutaneous metastatic melanoma and keloids, epidermolytic hyperkeratosis, Darier""s disease, pityriasis rubra pilaris, congenital ichthyosiform erythroderma, hyperkeratosis palmaris et plantaris, melasma, hyperpigmentation and similar disorders.
Further, the compounds of formula (I) are useful in suppressing the metabolism of exogenously administered and of endogenously formed 1xcex1,25-dihydroxy-vitamin D3 (calcitriol). The inhibitory activity of the compounds of formula (I) on the metabolic degradation of calcitriol may be evidenced by measuring the impact of said compounds on the calcitriol degradation in human foreskin keratinocytes, pig kidney cells and human hepatoma cells. In view of their inhibitory effect on the calcitriol metabolism, the compounds of formula (I) can be used in the treatment of vitamin D deficiency states. The xe2x80x9cclassicxe2x80x9d application of vitamin D compounds lies in the field of metabolic bone disorders. Calcitriol has also been described to influence the effects and/or production of interleukins. Further, calcitriol is of use in the treatment of diseases characterized by abnormal cell proliferation and/or differentiation, in particular, keratinization disorders such as those described hereinabove (Bouillon et al., Endocrine Reviews, 1995, 16, 200-257).
In view of the above described uses of the compounds of formula (I), it follows that the present invention provides a method of treating warm-blooded animals suffering from diseases which are characterized by an abnormal proliferation and/or abnormal differentiation of normal, preneoplastic or neoplastic cells, whether they are epithelial or mesenchymal; whether they are of ectodermal, endodermal or mesodermal origin. Said method comprises the systemic or topical administration of a retinoic mimetic amount of a compound of formula (I) effective in treating the above described disorders, in particular keratinization disorders such as psoriasis, optionally in the presence of an effective amount of a retinoic acid, a derivative or a stereochemically isomeric form thereof. The present invention further concerns a method of treating patients suffering from a pathological condition which may be beneficially influenced by the administration of calcitriol or a prodrug thereof, in particular keratinization disorders such as psoriasis, said method consisting of administering to a patient (a) an effective amount of calcitriol or a prodrug thereof and (b) an effective amount of a compound of formula (I).
Thus, the present invention also relates to compounds of formula (I) as defined hereinabove for use as a medicine, in particular, for use in the manufacture of a medicament for the treatment of keratinization disorders such as psoriasis. The present invention further relates to compounds of formula (I) as defined hereinabove in combination with a retinoic acid, a derivative or a stereochemically isomeric form thereof, or in combination with calcitriol or a prodrug thereof, for use as a medicine.
For ease of administration, the subject compounds may be formulated into various pharmaceutical forms. As appropriate compositions there may be cited all compositions usually employed for systemically or topically administering drugs. To prepare the pharmaceutical compositions of this invention, a retinoic mimetic effective amount of the particular compound, optionally in addition salt form, as the active ingredient is combined in intimate admixture with a pharmaceutically acceptable carrier, which may take a wide variety of forms depending on the form of preparation desired for administration. These pharmaceutical compositions are desirably in unitary dosage form suitable, preferably, for administration orally, rectally, percutaneously, or by parenteral injection. For example, in preparing the compositions in oral dosage form, any of the usual pharmaceutical media may be employed, such as, for example, water, glycols, oils, alcohols and the like in the case of oral liquid preparations such as suspensions, syrups, elixirs and solutions; or solid carriers such as starches, sugars, kaolin, lubricants, binders, disintegrating agents and the like in the case of powders, pills, capsules and tablets. Because of their ease in administration, tablets and capsules represent the most advantageous oral dosage unit form, in which case solid pharmaceutical carriers are obviously employed. For parenteral compositions, the carrier will usually comprise sterile water, at least in large part, though other ingredients, for example, to aid solubility, may be included. Injectable solutions, for example, may be prepared in which the carrier comprises saline solution, glucose solution or a mixture of saline and glucose solution. In the compositions suitable for percutaneous administration, the carrier optionally comprises a penetration enhancing agent and/or a suitable wettable agent, optionally combined with suitable additives of any nature in minor proportions, which additives do not cause any significant deleterious effects on the skin. Said additives may facilitate the administration to the skin and/or may be helpful for preparing the desired compositions. These compositions may be administered in various ways, e.g. as a transdermal patch, as a spot-on or as an ointment. Addition salts of compounds of formula (I) due to their increased water solubility over the corresponding base form, are obviously more suitable in the preparation of aqueous compositions.
As appropriate compositions for topical application there may be cited all compositions usually employed for topically administering drugs e.g. creams, gellies, dressings, shampoos, tinctures, pastes, ointments, salves, powders and the like. Application of said compositions may be by aerosol, e.g. with a propellent such as nitrogen, carbon dioxide, a freon, or without a propellent such as a pump spray, drops, lotions, or a semisolid such as a thickened composition which can be applied by a swab. In particular compositions, semisolid compositions such as salves, creams, gellies, ointments and the like will conveniently be used.
It is especially advantageous to formulate the aforementioned pharmaceutical compositions in dosage unit form for ease of administration and uniformity of dosage. Dosage unit form as used in the specification and claims herein refers to physically discrete units suitable as unitary dosages, each unit containing a predetermined quantity of active ingredient calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier. Examples of such dosage unit forms are tablets (included scored or coated tablets), capsules, pills, powder packets, wafers, injectable solutions or suspensions, teaspoonfuls, tablespoonfuls and the like, and segregated multiples thereof.
Other such compositons are preparations of the cosmetic type, such as toilet waters, packs, lotions, skin milks or milky lotions. Said preparations contain, besides the active ingredient, components usually employed in such preparations. Examples of such components are oils, fats, waxes, sufactants, humectants, thickening agents, antioxidants, viscosity stabilizers, chelating agents, buffers, preservatives, perfumes, dyestuffs, lower alkanols, and the like. If desired, further ingredients may be incorporated in the compositions. e.g. antiinflamatory agents, antibacterials, antifungals, disinfectants, vitamins, sunscreens, antibiotics, or other anti-acne agents.
The present invention also provides particular pharmaceutical or cosmetical compositions which comprise an inert carrier, an effective amount of a compound of formula (I) and an effective amount of a retinoic acid, a derivative thereof or a stereo-chemically isomeric form thereof. Said retinoic acid containing compositions are particularly useful for treating acne or for retarding the effects of aging of the skin and generally improve the quality of the skin, particularly human facial skin. Further, the invention also relates to particular pharmaceutical or cosmetical compositions which comprise an inert carrier, an effective amount of a compound of formula (I) and an effective amount of calcitriol or a prodrug thereof. The latter compositions are particularly useful in treating keratinization disorders.
The invention also relates to a product containing retinoic acid or a derivative thereof and a compound of formula (I) as a combined preparation for simultaneous, separate or sequential use in dermatological or oncological disorders. The invention also relates to a product containing calcitriol or a prodrug thereof and a compound of formula (I) as a combined preparation for simultaneous, separate or sequential use in disorders beneficially affected by calcitriol. Such products may comprise, for example, a kit comprising a container with a suitable composition containing a compound of formula (I) and another container with a composition containing calcitriol or a retinoid. Such a product may have the advantage that a physician can select on the basis of the diagnosis of the patient to be treated the appropriate amounts of each component and the sequence and timing of the administration thereof.
Those of skill in the treatment of the disorders described hereinabove could determine the effective therapeutic daily amount from the test results presented in the experimental part. An effective therapeutic daily amount would be from about 0.01 mg/kg to about 40 mg/kg body weight, more preferably from about 0.1 mg/kg to about 10 mg/kg body weight. It may be appropriate to administer the therapeutically effective dose once daily or as two, three, four or more sub-doses at appropriate intervals throughout the day. Said sub-doses may be formulated as unit dosage forms, for example, containing 0.1 mg to 500 mg of active ingredient per unit dosage form.
The exact dosage and frequency of administration depends on the particular compound of formula (I) used, the particular condition being treated, the severity of the condition being treated, the age, weight and general physical condition of the particular patient as well as other medication the patient may be taking, as is well known to those skilled in the art. Furthermore, it is evident that said effective daily amount may be lowered or increased depending on the response of the treated patient and/or depending on the evaluation of the physician prescribing the compounds of the instant invention. The effective daily amount ranges mentioned hereinabove are therefore only guidelines.
The following examples are intended to illustrate and not to limit the scope of the present invention.
Experimental Part
Of some compounds of formula (I) the absolute stereochemical configuration of the stereogenic carbon atom(s) therein was not experimentally determined. In those cases the stereochemically isomeric form which was first isolated is designated as xe2x80x9cAxe2x80x9d and the second as xe2x80x9cBxe2x80x9d, without further reference to the actual stereochemical configuration. Said xe2x80x9cAxe2x80x9d and xe2x80x9cBxe2x80x9d forms of those compounds of formula (I) wherein two stereogenic carbon atoms are present were separated in their pure steroechemically isomeric forms and designated as xe2x80x9cA1xe2x80x9d and xe2x80x9cA2xe2x80x9d, and xe2x80x9cB1xe2x80x9d and xe2x80x9cB2xe2x80x9d, without further reference to the actual stereochemical configuration.
As used hereinafter, xe2x80x9cTHFxe2x80x9d is defined as tetrahydrofuran, xe2x80x9cEtOAcxe2x80x9d is defined as ethylacetate, xe2x80x9cDIPExe2x80x9d is defined as diisopropyl ether and xe2x80x9cRTxe2x80x9d is defined as room temperate.
A) Preparation of the Intermediate Compounds